The present invention relates to chalcone and chalcone derivatives and analogs which are useful as angiogenesis inhibitors. The present compounds, which are inexpensive to synthesize exhibit unexpectedly good activity as angiogenesis inhibitors. The present invention also relates to the use of chalcone and its analogs as antitumor/anticancer agents and to treat a number of conditions or disease states in which angiogenesis is a factor.
Chalcone is a member or derivative of the phenylypropanoids, a large group of phenolic compounds synthesized only in plants, and predominantly derived from the aromatic amino acid phenylalanine. Phenylpropanoids and their derivatives perform diverse physiological functions in plants, and are represented by the polymeric lignins, the coumarins, suberins, stilbenes and flavonoids, as well as the chalcones, sometimes considered a sub-class of the flavonoids. In the predominant form of lignins, phenylpropanoids are second only to cellulose among the bio-molecules in total biosphere abundance. Lignins have a primarily structural role, but many compounds in this versatile group are biochemically active. The flavonoids, for example 
serve in many species as attractants of pollinators, UV protectors, insect repellents, signalling molecules and antibiotics, while the coumarins and stilbenes are implicated in the defense response of plants to pathogen ingress via their anti-microbial function effect.
Considering the other leg of the background of the present invention, angiogenesis may be defined as the development of a blood supply to a given area of tissue. The development of a blood supply may be part of normal embryonic development, represent the revascularization of a wound bed, or involve the stimulation of vessel growth by inflammatory or malignant cells. Sometimes angiogenesis is defined as the process through which tumors or inflammatory conditions derive a blood supply through the generation of microvessels. Although it may seem unremarkable that new growth of soft tissue requires new vascularization, the concept of angiogenesis as a key component of tissue growth and in particular, a key point of intervention in pathological tissue growth, had initially met with skepticism. By now the idea is well accepted.
Tumors need to induce formation of blood vessels to grow beyond a small size. A small tumor can use diffusion from nearby capillaries as its source of oxygenation, nutrition, and waste removal. However, once a tumor exceeds a critical mass, the center of the tumor becomes necrotic, because these crucial functions are no longer available. When a tumor gains the ability to generate new blood vessels, perfusion of a larger tumor mass is possible. The ability of malignant cells to form a large tumor and to metastasize is accompanied by decreased cellular differentiation and increased ability to produce angiogenic factors. Hence there is a strong interest in compounds that block angiogenesis and interrupt the growth process of malignant tumors, inflammatory lesions and benign neoplasms, as well as in compounds which stimulate cellular differentiation, and impede metastasis.
A tumor""s ability to become neovascularized permits rapid tumor growth and increases the likelihood of metastases; the transition from a quiescent tumor to an invasive tumor is accompanied by the crucial acquisition of angiogenic properties. The critical point may be characterized as the activation of a specific angiogenic switch. The phenotypic change from quiescence to virulence likely requires a change in the balance of angiogenic simulators and angiogenic inhibitors. The nature of the angiogenic switch is not known, however, growth factors and signal transduction are expected to be key components in the investigation of angiogenic regulatory mechanisms.
The first angiogenesis factor isolated was basic fibroblast growth factor (bFGF). Others include vascular endothelial growth factor (VEGF), interleukin-8, hepatocyte growth factor, platelet derived endothelial growth factor (PD-ECGF), and corticotropin-releasing hormone (CRH). The discovery of endogenous angiogenesis simulators naturally led researchers to ask whether there existed endogenous angiogenesis inhibitors. Interferon-alpha, which inhibits the replication of primary endothelial cells, was the first endogenous angiogenesis inhibitor discovered. Other naturally occurring small molecules which have been discovered to have anti-angiogenic activity include the retinoids and curcumin, a small molecular weight compound which is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. A summary of some major known angiogenesis stimulators and inhibitors is shown below.
Among the angiogenisis inhibitors, retinoids (vitamin A and its derivatives) play an important role in the development and differentiation of epidermal cells, as well as in reversing precancerous lesions. A number of references disclose retinoids being used in cancer prophylaxis and as inducers of cell differentiation. Kizaki et al., Seminars in Oncology 19(1):95-105(1992), for example, report that retinoids are potential anti-carcinogenic agents in many experimental models and that they inhibit growth and induce differentiation in transformed neoplastic cells. Unfortunately, the retinoids have a significant level of toxicity and administration of the known retinoid agents at therapeutic doses may be associated with undesirable side effects including headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dylipidemias, skin irritation, headache and hepatotoxicity. Accordingly, there exists a need to provide novel compounds having retinoid activity but which have less toxicity and/or side effects.
Chalcone compounds (3-oxo-1-propenyl derivatives) are sometimes classified as derivatives of the retinoids, and also of the flavones or flavonoids. Some flavones and chalcones have been found to have anti-tumor properties. Compounds related to coumarin, a flavone isolate from the widely used spice turmeric, are known to inhibit the carcinogenicity of carcinogens: Coumarin has been tested for treatment of melanoma. Certain chalcones and flavonoids, including biochanin A, are also known to exhibit anti-mitotic action in inhibiting cell division; e.g. in Shibata, Anti-tumorgenic chalcones, Stem Cells, 12:44-62, 1994; Edwards et al., Chalcones: A New Class of Antimitotic Agents, J. Med. Chem., 33:1948-1954, 1990; and Varma, Dietary Bioflavonoids, Chalcones and Related Alkenones in Prevention and Treatment of Cancer, Nutrition, 12; 643 (1996).
It is an object of the invention to provide compounds and pharmaceutical compositions which exhibit activity as inhibitors of angiogenesis.
It is another object of the invention to provide compounds and pharmaceutical compositions which can be used to treat tumors and/or cancer.
It is an additional object of the present invention to provide compounds and pharmaceutical compositions for use in treating angiogenic skin disorders such as psoriasis, venous ulcers, acne, rosacea, warts, eczema, hemangiomas, lymphangiogenesis, among numerous others, as well as internal malignancies (e.g., colon, cervical, bladder), oral malignancies, cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma and melanoma and inflammation.
It is yet another object of the invention to provide a method of treating tumors and/or cancer as well as the above-referenced angiogenic skin disorders.
It is still another object of the present invention to provide compounds which exhibit anti-angiogenesis and/or anti-tumor activity and are relatively inexpensive to synthesize.
It is yet another object of the present invention to enhance the inhibition of Map kinase and the phosphoinositide cascade.
Any one or more of these and/or other objects of the present invention may be readily gleaned from a description of the invention which follows.
The present invention relates to compounds or pharmaceutically acceptable salts, thereof of the formula: 
Where n is 0, 1 or 2;
Q and T are independently selected from a chemical group of the formula: 
xe2x80x83Where A, B, C1, D, E, G, J, K, L amd M are independently selected from H, a C1-C3 alkyl group, a halogen, an OR group, COOH, COOR1, an alkylene ester group according to the structure xe2x80x94(CH2)mCOOR1 or a CF3 group;
R is a C1-C4 alkyl group (preferably, C1-C3 alkyl), a benzyl or phenyl group or a 
xe2x80x83group;
R1 is a C1-C20 alkyl group, preferably a C1-C3 alkyl group;
R2 is a C1-C20 alkyl group, preferably a C1-C3 alkyl group;
Z is 0, S, Nxe2x80x94H, NCH3, NCH2CH3, or CH2;
V is a group according to the structure: 
xe2x80x83Where A, B, C1, D and Y are the same as set forth above;
U is H or halogen;
W is COR1, CN or COOR1;
R1 is a C1-C4 alkyl group (preferably, a C1-C3 alkyl group) or a benzyl or phenyl group;
R2 is O, S, NH, NCH3, NCH2CH3, or CH2;
With the proviso that n is not 0 for both Q and T and when n is 1 for Q and T, Qxe2x80x94V or Vxe2x80x94T may together form a structure according to the formula: 
xe2x80x83Where Z is the same as set forth above.
The present invention is also directed to pharmaceutical compositions comprising an effective amount of one or more compounds according to the present invention (including a pharmaceutically acceptable salt, thereof), optionally in combination with a pharmaceutically acceptable carrier, excipient or additive.
The present invention is also directed to methods for the treatment of tumors and/or cancer, internal and oral malignancies, angiogenic skin disorders and inflammation, including chronic inflammatory disease comprising administering an effective amount of one or more compounds according to the present invention to a patient in need of therapy, thereof.
More particularly, the present invention relates to methods for inhibiting the growth of neoplasia, including a malignant tumor or cancer comprising exposing the neoplasia to an inhibitory or therapeutically effective amount or concentration of at least one of the disclosed compounds. This method may be used therapeutically, in the treatment of neoplasia, including cancer or in comparison tests such as assays for determining the activities of related analogs as well as for determining the susceptibility of a patient""s cancer to one or more of the compounds according to the present invention. Treatment of internal malignancies such as eye or ocular cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, among numerous others, and oral malignancies are also contemplated by the present invention.
Methods for treating angiogenic skin disorders such as psoriasis, acne, rosacea, warts, eczema, hemangiomas, lymphangiogenesis as well as inflammation such as chronic inflammatory disease, including arthritis, lupus and scleroderma are also contemplated by the present invention, such methods comprising administering a therapeutically effective amount of one or more of the disclosed compounds to a patient in need of such treatment.